The metal transcription factor-1 (MTF-1) is a metal and redox-sensitive protein that is essential for embryonic development and involved in the transcriptional regulation of a growing number of tumor-related proteins including metallothionein, placenta growth factor, zinc transporter-1, glucose-6-phosphate, dehydrogenase, and matrix metalloproteinases. This laboratory has found MTF-1 to be highly expressed in human carcinomas and to be positively associated with the metastatic potential of human breast cancer cell lines. The genetic loss of MTF-1 results in suppression of experimental tumor growth and angiogenesis through enhanced deposition of extra-cellular matrix, caused in part by increased expression and activation of the transforming growth factor-pi and tissue transglutaminase, and attenuated expression of some matrix metalloproteinases. This group has also found MTF-1 to be involved in chemo- and radio-resistance, to contribute to the accumulation of the hypoxia-inducible factor-1 a (HIF-la) in response to hypoxia, and to be implicated in hypoxia-inducible signaling through two central mitogen activated protein kinase pathways. The first set of studies (Specific Aim 1)will address the putative role of MTF-1 in conferring chemo- and radio-resistance and translational relevance using human xenografts. It will also assess downstream contributions from HIF-la, and other specific signaling pathways. Aim 2 will define the underlying molecular mechanisms involved hi the regulation of HEF-la accumulation by MTF-1. An understanding of this regulatory pathway is important since HIF-la is believed to play a key role in tumorigenesis, angiogenesis and therapy resistance. Aim 3 will address the interaction between tumor and host cells in the initiation and progression of tumor growth as a function of MTF-1 expression utilizing MTF-1 conditional knockout mice and conditional knockout cell lines. The relative roles of MTF-1 and HIF-la in angiogenesis and initiation of tumor development, using the novel dorsal skin flap window chamber model, will also be addressed. An understanding of these MTF-1-dependent properties should aid in the development of novel prognostic and new modalities for neoplastic diseases.